The present disclosure is generally directed to methods of targeting apurinic/apyrimidinic endonuclease1/redox effector factor 1 (APE1/Ref-1). More particularly, by inhibiting APE1/Ref-1, hypoxia-mediated signaling is inhibited, thereby decreasing survival and invasion of tumor cells exposed to hypoxic conditions. In one particular embodiment, the present disclosure is directed to methods of administering the combination of an inhibitor of APE1/Ref-1 and an inhibitor of carbonic anhydrase IX (CA9).
Half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) die within a year due to their disease. Treatment with chemotherapy has not changed the natural course of this disease. Several mechanisms are proposed to play a role in the aggressive, treatment-resistant phenotype of PDAC, including adaptation to hypoxia, which leads to increased potential for metastasis and impairs the efficacy of chemotherapy and radiotherapy. One of the main sensors of oxygen in cells is Hypoxia-Inducible Factor-1α (HIF-1α), a transcription factor that is rapidly degraded under normoxic conditions, but upregulates a number of genes under hypoxic conditions that contribute to survival, metastasis, and angiogenic signaling in the tumor microenvironment. One of the most notable HIF targets is carbonic anhydrase IX (CA9), which promotes tumor cell survival and metastasis by maintaining a steady intracellular pH while acidifying the microenvironment, thereby encouraging epithelial-mesenchymal transition and contributing to extracellular matrix degradation.
Apurinic/apyrimidinic endonuclease1/redox effector factor 1 (APE1/Ref-1) is a multi-function protein that possesses a DNA repair function in base excision repair, as well as the ability to reduce transcription factors and enable them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in preventing apoptosis, survival mechanisms, and hypoxia signaling, including HIF-1α.
Based on the foregoing, the present disclosure is directed to interfering with APE-1/Ref-1 to further interfere with HIF-1α-mediated signaling, leading to a decreased survival and invasion of tumor cells exposed to hypoxic conditions.